Vitamin C reduces the severity of common colds: a meta-analysis

Background Randomized trials have shown that vitamin C shortens the duration of common colds. Some trials reported greater effects on severe cold symptoms compared with mild symptoms. This review systematically compares the effects of vitamin C on severe and mild common cold symptoms. Methods We included all placebo-controlled trials of orally administered vitamin C in doses of at least 1 g/day for the common cold for people in good health at baseline. The analysis was restricted to trials which reported both the total duration of the common cold, and the severity of the common cold measured using severity scales, the duration of more severe stages of the cold, or proxies for severe colds such as days indoors. Findings were pooled using the inverse variance, fixed effect options of the metacont function of the R package meta to calculate the ratio of means estimate. Results Fifteen comparisons from 10 trials which reported both mild and severe symptoms were identified. All trials were randomized and double-blind. Compared to placebo, vitamin C significantly decreased the severity of the common cold by 15% (95% CI 9–21%). The direct comparison of the effect of vitamin C on mild and severe symptoms was limited to five comparisons which found that vitamin C had a significant benefit on the duration of severe symptoms. In this subset, there was a significant difference in the size of the effect of vitamin C on the overall duration of colds versus the duration of severe colds (P = 0.002), and vitamin C had no significant effect on the duration of mild symptoms. Conclusions The common cold is the leading cause of acute morbidity and a major cause of absenteeism from work and school. However, absenteeism is dependent on the severity of symptoms. The finding that vitamin C may have a greater effect on more severe measures of the common cold is therefore important. Further research on the therapeutic effects of vitamin C on the common cold should measure outcomes of differing levels of severity. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-023-17229-8.


Search for the controlled trials
Calculation of SD for absence from school in the Ludvigsson (1977) trial Table S1.Characteristics of included studies

Exclusion of the three largest trials
In Figure S1 below, the three largest trials by Anderson (1972), Ludvigsson (1977L) and Pitt (1979) are excluded from the analysis shown in Figure 2 of the report, yet there remains a significant 19% effect on the severe common cold outcomes.Anderson (1975) See data in Additional file 2 and in the Anderson et al (1975) report [58].

Calculation of SD for absence from school in the Ludvigsson (1977) trial
See calculations on sheet "Ludvigsson" and data on Table V in Ludvigsson et al. (1977) [30] From Table V: Absence from school, vitamin C 1000 mg/day group: Total number of common cold episodes: 1.63*80 = 130 Number of common cold episodes with Absence from school: 0.28*80 = 22.Number of (mild) common cold episodes without Absence from school: 108 = 130 -22.Mean and SD for Absence from school among the 22 is reported in Table V.
Let us assume that there are 130 observations distributed between two groups of 108 observations all with value 0 (mean 0 and SD 0) 22 observations with mean 2.68 and SD 1.88 (Table V in [30]).
The SD for all the 130 observations can be calculated as follows: The whole group has sum of squares over 130 with Ẍ being the overall mean: We can divide the SS into two parts: 22 and 108: Here Ẋ22 = 2.68 for the subgroup of the 22; and Xi = 0 for all the 108 The term (Xi -Ẋ22) sums to 0, since Ẋ22 is the mean of Xi in the group of the 22.Thus, Thus, the dose on the first 3 days of a disease was 4 g/d.
"Particular care was taken to ensure that the vitamin and placebo tablets were indistinguishable in appearance and taste.Pure ascorbic acid has a very strong and characteristic flavour which is difficult to imitate, and we therefore used a formulation containing 200 mg of sodium ascorbate, 75 mg of ascorbic acid and an artificial orange flavouring.The taste of this formulation was well matched by a placebo preparation containing 30 mg of citric acid and the same orange flavouring and fillers.The effectiveness of the matching was established by asking 30 individuals to taste both tablets, and using pure ascorbic acid as reference, to judge which tablet contained the vitamin.Sixteen persons selected the placebo tablet and 14 the vitamin tablet.The effectiveness of the matching was verified at the end of the main study by the answers to the question "Do you think you have been on the vitamin or placebo tablet?".Approximately half of the 818 subjects answered "Don't know", and the remainder were divided almost equally between those who guessed correctly and those who did not" (p 504).

Outcomes Total duration of cold symptoms:
Duration of all colds "symptoms present" (p 505; Table II).

Common cold severity outcome:
Duration of "confined to house" (p 505; Table II).

Notes
Funding: not reported

Bias
Authors' judgement Support for judgement

Random sequence generation (selection bias)
Low risk "Subjects were allocated to vitamin and placebo in a strictly double-blind randomized manner" (p 504).

Allocation concealment (selection bias)
Low risk See above.

Baseline balance Low risk
Table 1 shows balance for age, sex, student status, smokers, cold frequency, contact with young children, frequency in crowds, consumption of fruit juices.
Blinding of participants and personnel (performance bias)

Low risk
See above and "... the code was not broken until after all the data had been transferred to punch cards and initial tabulations carried out" (p 504).

Blinding of outcome assessment (detection bias)
Low risk See above and "[blinded] Subjects were instructed to record each day whether they were sick or well" (p 504-5),

Incomplete outcome data (attrition bias)
Low risk 182 drop outs out of initial full complement of 1000.Almost all were contacted and most dropped out because of loss of interest or inability to remember to take tablets.(p 504) It is not clear whether the drop outs were evenly distributed between the vitamin C and placebo groups, but the relative distribution of recorded characteristics was the same as the main group (p 505).There were 28 dropouts "because of suspected side effects, distributed almost equally between the vitamin (15) and placebo groups ( 13)" (p 507).

Selective reporting (reporting bias)
Low risk Relevant outcomes were reported extensively.Incidence of colds, duration of "symptoms present", duration of "confined to house", "days off work" and proportions without symptoms, without confined to house, and without days off work.
Vitamin C and placebo indistinguishable?

Low risk
See above: "The taste of this [vitamin C tablet] formulation was well matched by a placebo preparation...The effectiveness of the matching was established by asking 30 individuals to taste both tablets ..." (p 504).

Contamination Unclear risk
There was insufficient reporting to enable assessment.However, the effect of vitamin C was greater on participants who consumed less fruit juice compared with those who consumed more, which is consistent with baseline vitamin C intake modifying the effects of supplementation.Thus, the dose on the 1st day of a disease was 4 g/d.

Participants
"instructed to take four of their "Daily" tablets each day (one qid or two bid) plus 12 of their Extra tablets [0.25 g] (two every hour) on the first day of any illness" (p 32)."All three tablets were of a similar size and shape, and an initial 'taste test' carried out with the help of a number of colleagues demonstrated that they were reasonably well matched in flavour, texture and appearance.This was confirmed at the end of the trial by asking the participants whether they thought their daily tablets had contained vitamin or placebo.Approximately half of each group answered "don't know", and of the remainder, approximately two thirds answered "vitamin" and one third "placebo", irrespective of the actual nature of their tablets" (p 32).

Outcomes Total duration of cold symptoms:
Duration of all colds "days of symptoms" (p 33; Table II).

Notes
There were problems with the placebo group #6 so that baseline was inconsistent with the baselines of six vitamin C groups (Hemilä 2006: p 40,

Bias
Authors' judgement Support for judgement

Random sequence generation (selection bias)
Low risk "Bottles were numbered in accordance with a computer-generated list of numbers randomized in groups of eight, then given out in consecutive order as subjects registered" (p 33).

Baseline balance Low risk
Compared with the placebo group #4, Table 2 shows balance for age, sex, smoking, frequency of usual cold episodes, usual days indoors, usual days off work, contact with children, frequency in crowds, daily juice consumption.

Blinding of participants and personnel (performance bias)
Low risk "double-blind" (p 31).

Blinding of outcome assessment (detection bias)
Low risk Blinded "subjects were asked to complete a checklist of the symptoms present on each day of illness" (p 33).

Incomplete outcome data (attrition bias)
Low risk The dropout rates were 37% (163/440) in the vitamin C group and 35% (155/440) in the placebo group #4.Of the total 1171 subjects who dropped out of the study, 74 cited side effects as the reason (p 35).One of the commonest reasons for dropping out was difficulty in swallowing the large tablets (p 34).
Selective reporting (reporting bias) Low risk Relevant outcomes were reported extensively.Incidence of colds, duration of "symptoms present", "days indoors", "days off work".
Vitamin C and placebo indistinguishable?
Low risk "All three tablets were of a similar size and shape, and an initial 'taste test' carried out with the help of a number of colleagues demonstrated that they were reasonably well matched in flavour, texture and appearance" (p 32).

Contamination Unclear risk
There was insufficient reporting to enable assessment.

Participants
Australian males and females.Age mean 25 y (range 14 to 64 y; 36 pairs under 18 years, 34 pairs aged 18 to 30 years, and 25 pairs aged 30+ years).38 male and 57 female pairs of twins in total.This comparison is for 44 twin pairs living apart.
Interventions 1 g/d vitamin C for 100 days."The treatment group received 1 g of ascorbic acid per day in the form of Redoxon® tablets (Roche Products), and the control group received a placebo with the same ingredients in different proportions but with lactose substituted for ascorbic acid.Quality of matching of the active and placebo tablets was checked for both appearance and taste by triangular discrimination tests on 60 pharmacology students.Two of one kind of tablet and one of the other were presented to the subject who had to pick the odd one out.It was found that subjects could pick a difference between the appearance of the dry tablets (chi2 = 39.7) but when these were dissolved in water they were not able to pick a difference at better than chance level (chi2 = 0.68).Having decided on the solution that tasted different, subjects were asked to identify it as active or placebo and in fact fewer than expected by chance were able to identify the solution correctly.It was concluded that the placebo was well matched in important respects and subsequent results bore this out" (p 250)."In addition ..., both groups received multivitamin capsules containing 70 mg vitamin C.This was to ensure that any observed treatment effect could reasonably be attributed to the pharmacologic dose of vitamin C and not to alleviation of dietary deficiency" (p 250).

Outcomes Total duration of cold symptoms:
Common cold duration (p 252; Table 2).

Notes
The SD for duration and were not published and the SDs were calculated from the P values, setting the ratio of SD in the vitamin C and placebo groups equal with the ratio of mean outcomes in the vitamin C and placebo groups, see Additional file."Among the twins living together, those taking vitamin C had a significantly higher incidence, total duration, and total severity of colds ...Among the pairs living apart there were 9 significant treatment differences ... all of these favoured the vitamin C group" (p 252).Funding: Roche Products, supplied the tablets and gave financial support to cover postage costs.

Bias
Authors' judgement Support for judgement

Random sequence generation (selection bias)
Low risk "One twin of a pair was assigned at random to the treatment groups and the other to the control group" (p 250).

Allocation concealment (selection bias)
Low risk "The experiment was "double-blind" in that neither the subjects nor the experimenters involved with the subjects or with the analysis of the results knew which group was which until the experiment and the analysis were completed" (p 250).

Baseline balance Low risk Twins
Blinding of participants and personnel (performance bias) Low risk See above.

Blinding of outcome assessment (detection bias)
Low risk See above.

Incomplete outcome data (attrition bias)
Low risk "Of the 125 pairs of twins who began the trial, we have analyzed cold data for 95 pairs" (p 250) Because of the pairing, the dropout of a pair cannot generate a systematic bias between the groups.
Selective reporting (reporting bias) Low risk Incidence of colds, duration of colds and severity of colds reported.
Vitamin C and placebo indistinguishable?
Low risk "matching of the active and placebo tablets was checked for both appearance and taste" (p 250).

Contamination High risk
Placebo group received a multi-vitamin tablet containing 70 mg/d vitamin C. In addition, no effect of vitamin C was seen among twins who lived together, whereas a significant benefit of vitamin C was seen among twins living apart, which most probably is explained by swapping of tablets among twins living together.

Contamination
High risk Estimated pre-supplementation vitamin C intake in the placebo group was 227 mg/d, and in the vitamin C group 312 mg/d (Report 1998: Table 2; Thesis 1996: Table 15).
Selective reporting (reporting bias) Low risk Incidence of colds, duration of nasal and throat/chest colds, and severity of colds were reported.
Vitamin C and placebo indistinguishable?
Low risk "Vitamin C and placebo were in identical capsules, so taste did not enter into the equation...In our pre-briefing to the troops, we believe that we told the troops that they would all be getting vitamin C but at different doses" (email Radomski 12 September 2009).

Contamination
Low risk "it was determined that the RP-4 rations  on which the men were living, apparently provided a maximum of 37-41 mg Vitamin C per day in a single fruit-drink mix" (p 4)."The whole-blood ascorbate levels of individuals receiving a Vitamin C supplement were increased well above normal (100-150%)" (p 8).

Fig. S1 .
Fig. S1.Exclusion of the three largest trials Fig. S2.Comparison of the effects of vitamin C on severe and mild (overall) common cold symptoms in 15 trial arms Fig. S3.Sensitivity analysis of Fig. 2 using the SMD scale Fig. S4.Sensitivity analysis of Fig. 2 using the random-effects meta-analysis Fig. S5.Effect of vitamin C on confined indoors and any symptoms inAnderson (1975)

Fig. S1 .
Fig. S1.Exclusion of the three largest trials .49/129 = 1.593SD130 = √Var = 1.262Interventions 1 g/d vitamin C regularly for 3 months and 3 g/d vitamin C extra for the first 3 days of illness.
Canadian adults, both sexes, recruited from staff of large hospitals and business organisations (p 32)."Although subjects were recruited from a variety of occupations, it should be stressed that they were not a representative sample of the general population, since only those persons who usually suffered at least one episode of illness between December and March (but were otherwise in good general health) were accepted" (p 32).
Interventions1 g/d vitamin C regularly for 3 months and 3 g/d vitamin C extra at onset of illness on the 1st day only.